Characterization of ATM mutations in 41 Nordic families with Ataxia Telangiectasia

The Ataxia Telangiectasia Mutation (ATM) gene is mutated in the rare recessive syndrome Ataxia Telangiectasia (AT), which is characterized by cerebellar degeneration, immunodeficiency, and cancer predisposition. In this study, 41 AT families from Denmark, Finland, Norway, and Sweden were screened for ATM mutations. The protein truncation test (PTT), fragment length and heteroduplex analyses of large (0.8–1.2 kb) cDNA fragments were used. In total, 67 of 82 (82%) of the disease‐causing alleles were characterized. Thirty‐seven unique mutations were detected of which 25 have not previously been reported. The mutations had five different consequences for the ATM transcript: mutations affecting splicing (43%); frameshift mutations (32%); nonsense mutations (16%); small in‐frame deletions (5%); and one double substitution (3%). In 28 of the probands mutations were found in both alleles, in 11 of the probands only one mutated allele was detected, and no mutations were detected in two Finnish probands. One‐third of the probands (13) were homozygous, whereas the majority of the probands (26) were compound heterozygote with at least one identified allele. Ten alleles were found more than once; one Norwegian founder mutation constituted 57% of the Norwegian alleles. Several sequence variants were identified, none of them likely to be disease‐causing. Some of them even involved partial skipping of exons, leading to subsequent truncation of the ATM protein. Hum Mutat 16:232–246, 2000. © 2000 Wiley‐Liss, Inc.